Glycogen storage disease type II (GSD II) is a classical lysosomal storage disorder, characterized by lysosomal accumulation of glycogen and tissue damage, primarily in muscle and heart (Hirschhorn, R. and Reuser, A. J. (2001) In The Metabolic and Molecular Basis for Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D. Eds.), pp. 3389-3419. McGraw-Hill, New York). The underlying enzyme deficiency is acid α-glucosidase (GAA). In severe, infantile GSD II progressive cardiomyopathy and myopathy lead to cardiorespiratory failure and death by 1 year of age. In milder, juvenile and adult-onset GSD II, progressive weakness and respiratory failure are disabling and death from respiratory failure occurs.
Animal models for human lysosomal acid α-glucosidase (hGAA) deficiency accurately mimic GSD II, and the efficacy of approaches to gene therapy for GSD II can be evaluated in these systems. The GAA knockout (GAA-KO) mouse model accumulated glycogen in skeletal and cardiac muscle, and developed weakness and reduced mobility (Raben, N., et al. (1998) J. Biol. Chem. 273:19086-19092, Bijvoet, A. G., et al. (1998) Hum. Mol. Genet. 7:53-62). The administration of recombinant GAA to a GAA-KO mouse demonstrated uptake of GAA by skeletal muscle, presumably through receptor-mediated uptake and delivery of GAA to the lysosomes (Bijvoet, A. G. et al., (1998) Hum. Mol. Genet. 7:1815-1824). The Japanese quail model is similar to juvenile-onset GSD II, and has been treated successfully with recombinant enzyme replacement (Kikuchi, T., et al. (1998) J. Clin. Invest. 101:827-833). Enzyme therapy has demonstrated efficacy for severe, infantile GSD II; however the benefit of enzyme therapy is limited by the need for frequent infusions and the development of inhibitor antibodies against recombinant hGAA (Amalfitano, A., et al. (2001) Genet. In Med. 3:132-138). As an alternative or adjunct to enzyme therapy, the feasibility of gene therapy approaches to treat GSD-II have been investigated (Amalfitano, A., et al., (1999) Proc. Natl. Acad. Sci. USA 96:8861-8866, Ding, E., et al. (2002) Mol. Ther. 5:436-446, Fraites, T. J., et al., (2002) Mol. Ther. 5:571-578, Tsujino, S., et al. (1998) Hum. Gene Ther. 9:1609-1616).
Administration of an adenovirus (Ad) vector encoding hGAA that was targeted to mouse liver in the GAA-KO mouse model reversed the glycogen accumulation in skeletal and cardiac muscle within 12 days through secretion of hGAA from the liver and uptake in other tissues (Amalfitano, A., et al., (1999) Proc. Natl. Acad. Sci. USA 96:8861-8866). Antibodies against hGAA abbreviated the duration of hGAA secretion with an Ad vector in liver, although vector DNA and hGAA persisted in tissues at reduced levels for many weeks (Ding, E., et al., (2002) Mol. Ther. 5:436-446). Introduction of adeno-associate virus 2 (AAV2) vectors encoding GAA normalized the GAA activity in the injected skeletal muscle and the injected cardiac muscle, and glycogen content was normalized in muscle when an AAV1-pseudotyped vector was administered with improved muscle transduction (Fraites, T. J., et al. (2002) Mol. Ther. 5:571-578). Muscle-targeted Ad vector gene therapy was attempted in the Japanese quail model, although only localized reversal of glycogen accumulation at the site of vector injection was achieved (Tsujino, S., et al. (1998) Hum. Gene Ther. 9:1609-1616).
Neonatal gene therapy may have greater efficacy than administration later in life, as evidenced by experiments in several rodent disease models. An AAV vector administered intravenously on the second day of life in β-glucoronidase deficient (Sly disease) mice produced therapeutically relevant levels of β-glucoronidase and corrected lysosomal storage in multiple tissues, including liver and kidney (Daly, T. M., et al. (1999) Proc. Natl. Acad. Sci. USA 96:2296-2300). Similarly, intramuscular injection of the AAV vector produced sustained, therapeutic levels of expression of β-glucoronidase and eliminated lysosomal storage in muscle and liver (Daly, T. M., et al., (1999) Hum. Gene Ther. 10:85-94). AAV vector DNA persisted in muscle and in transduced areas of the liver following neonatal intramuscular injection in the Sly disease mouse (Daly, T. M., et al. (1999) Hum. Gene Ther. 10:85-94). The number of AAV vector particles administered to neonatal Sly mice was approximately 100-fold less than was needed to produce therapeutically relevant levels of proteins in adult mice (Kessler, P. D., et al. (1996) Proc. Natl. Acad. Sci. USA 93:14082-14087, Herzog, R. W., et al. (1997) Proc. Natl. Acad. Sci. USA 94:5804-5809, Nakai, H., et al. (1998) Blood 91:4600-4607, Snyder, R. O., et al. (1997) Nat. Genet. 16:270-276, Koeberl, D. D., et al. (1999) Hum. Gene Ther. 10:2133-2140, Snyder, R. O., et al. (1999) Nat. Med. 5:64-70, Herzog, R. W. et al. (1999) Nat. Med. 5:56-63).
There is a need in the art for improved methods of producing lysosomal polypeptides such as GAA in vitro and in vivo, for example, to treat lysosomal polypeptide deficiencies. Further, there is a need for methods that result in systemic delivery of GAA and other lysosomal polypeptides to affected tissues and organs.